Project Summary Cerebral small vessel disease (SVD) refers to a group of conditions that affect the small arteries, arterioles, venules, and capillaries of the brain. They account for up to 30% of strokes and are a leading cause of age- related and hypertension-related cognitive decline and disability. Intracerebral hemorrhage (ICH) is a consequence of cerebral SVD. Current treatment options are limited and understanding the pathomechanism of the underlying ICH is necessary for discovery and development of effective therapeutics. While studies have identified genetic causes and risk factors for some forms of sporadic and familial forms of ICH, there exists considerable need to determine the underlying causes of most forms of cerebral SVD. We have discovered that mutations in type IV collagen alpha 1 (COL4A1) cause multisystem disorders, including cerebrovascular disease presenting as porencephaly and prenatal, perinatal, and recurrent multifocal ICHs. Our objective is to use genetic models and pharmacologic interventions to understand the role of COL4A1 in the pathogenesis of cerebral SVD.